Postnatal Oxytocin Treatment Improves Survival and Improves Behavioral Outcomes in an Animal Model of Neonatal Abstinence Syndrome

Abstract

Objective To investigate the therapeutic effect of the neuropeptide oxytocin in an animal model of neonatal abstinence syndrome. Hypothesis Prenatal exposure to drugs of abuse (eg. opioids and benzodiazepines) results in a severe withdrawal syndrome known as neonatal abstinence syndrome (NAS). NAS is a serious health problem with increasing prevalence. Standard of care pharmacological intervention consists of morphine, methadone, buprenorphine, clonidine, and phenobarbital. Safer and more effective treatments are urgently needed. The neuropeptide oxytocin has been shown to reverse drug and alcohol withdrawal syndromes in adult animals and humans. Here, we examined the effect of postnatal oxytocin treatment on survival and behavioral outcomes in neonatal rats prenatally exposed to opioids or benzodiazepines. Methods Pregnant Sprague-Dawley rats were injected subcutaneously with escalating doses of morphine (10-50 mg/kg/day) or diazepam (2-15 mg/kg/day) starting at gestational day seven through parturition. Upon delivery, rat pups received daily subcutaneous injections of 2 mg/kg oxytocin or saline for the first 10 postnatal days and survival was measured. A second cohort of morphine and diazepam exposed rat pups received injections of 0.3, 1, or 2 mg/kg oxytocin or saline for the first 10 postnatal days and survival was assessed for 30 days. Surviving animals were subjected to a battery of behavioral assessments between postnatal day 30 and 45 to determine how early life oxytocin treatment impacts neurocognitive outcomes. These assessments included a Locomotor Assay, Light-Dark Box Test, Passive Avoidance Task, and Social Interaction Test. Animals were then sacrificed, blood was collected and processed, and glucose oxidase, coritcosterone, and aldosterone was measured using Enzyme Immunoassay (EIA). Results In the first cohort of animals exposed to morphine prenatally, survival was significantly improved with 2 mg/kg oxytocin treatment compared to saline (100% vs 66.67%; P=0.008). The same pattern was observed with animals exposed to diazepam prenatally (100% vs 66.5%; P=0.0149). In the second cohort of animals exposed to morphine prenatally, all doses of oxytocin (0.3, 1, and 2 mg/kg) improved survival compared to saline (88.89%, 100%, 100% vs 50%, respectively; P<0.0001). A similar pattern of improved survival following the two highest doses of oxytocin, but not 0.3 mg/kg, was observed with animals exposed to diazepam prenatally (68.75%, 100%, 100% vs 62.5%, respectively; P=0.0176). Preliminary findings for improvements in learning and memory and social behavior were also observed. No differences in the measured biological outcomes was observed. Conclusions These findings provide insights in to the potential for oxytocin as a novel treatment option for NAS. Given the high unmet need in NAS and the established safety profile of oxytocin, clinical trials appear warranted.